Pharmaceutical compositions comprising fatty acid esters

ABSTRACT

The present invention relates to an injectable, pharmaceutical composition comprising a C 1-6  alkyl ester of a C 10-20  fatty acid. In an embodiment, the fatty acid is ethyl oleate, isopropyl oleate, ethyl myristate, or isopropyl myristate. These compositions are useful for the delivery of anti-psychotic drugs.

RELATED APPLICATIONS

This application claims priority from U.S. Provisional PatentApplication 61/612,734, filed on Mar. 19, 2012, the contents of whichare incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to an injectable, pharmaceuticalcomposition comprising a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid. In anembodiment, the fatty acid is ethyl oleate, isopropyl oleate, ethylmyristate, or isopropyl myristate. These compositions are useful for thedelivery of anti-psychotic drugs.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 4,734,416 and 5,006,528 discloses aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinoneor 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril, as an atypical antipsychotic agent useful in the treatmentof schizophrenia, bipolar disease, depression and other CNS disorders.Aripiprazole has the following chemical structure:

Aripiprazole is sold under the tradename Abilify®. It acts as a dopamineD₂ partial agonist, serotonin 5-HT_(1A) receptor agonist and is anantagonist of the serotonin 5-HT_(2A) receptor. Abilify® is currentlyadministered orally on a once-a-day dosing schedule as Abilify®(aripiprazole) Tablets, Abilify Discmelt® (aripiprazole) OrallyDisintegrating Tablets and Abilify® (aripiprazole) Oral Solution. In oneembodiment, Abilify® Injection for intramuscular use is a rapid-actingsolution product for treating agitation associated with schizophreniaand bipolar disease. Poor and variable patient compliance with aonce-a-day dosing schedule of psychiatric drugs has been reported.

Efforts have been made to provide drug dosage forms that may increasethe compliance of patients and thereby lower the rate of relapse in thetreatment of schizophrenia. U.S. Pat. No. 7,807,680 and U.S. PublicationNo. 2005/0032811 describe long-acting aripiprazole sterile injectableformulations. Studies on aripiprazole free base injections showed aprolonged pharmacokinetic profile, but incidents of unacceptable(moderate to severe) tissue irritation following IM and SC injectionwere also reported.

U.S. Pat. No. 7,115,587 discloses an injectable formulation thatdelivers an aripiprazole solution complexed with a substitutedβ-cyclodextrin to the muscular site with diminished irritation ascompared to injectable suspensions containing uncomplexed aripiprazole.The Abilify® injection for intramuscular use is a single-dose, ready touse vial consisting of 9.75 mg/1.3 ml of aripiprazole and 150 mg/ml ofsulfobutylether β-cyclodextrin. Formulation challenges due to drugloading and poor solubility of aripiprazole in β-cyclodextrin at neutralpH have been reported.

Olanzapine(1,2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine)is a second generation antipsychotic drug marketed as Zyprexa®. It isuseful for the treatment of disorders such as schizophrenia, bipolardisorder, psychotic depression and Tourette's syndrome. This activepharmaceutical ingredient acts as an antagonist on 5-HT₂ serotoninreceptors as well as the D₁/D₂ dopamine receptors, while also exhibitinganticholinergic and antimuscarinic properties. Olanzapine belongs to thebenzodiazepine family, and has the following structure:

This compound is disclosed, for example, in U.S. Pat. Nos. 5,229,382 and6,169,084. An extended release intramuscular injection productcontaining the water-insoluble salt olanzapine pamoate monohydrate isapproved for use in schizophrenia. Like aripiprazole, olanzapine cancause adverse site reactions when injected into a subject.

SUMMARY OF THE INVENTION

There exists a need for improved pharmaceutical compositions ofaripiprazole, olanzapine, prodrugs thereof, and other anti-psychoticagents, for extended release use, thereby improving patient complianceand optimizing the pharmacological profile of the active agent.

Provided herein are pharmaceutical compositions comprising (a) awater-insoluble antipsychotic agent, and (b) a C₁₋₆alkyl ester of aC₁₀₋₂₀ fatty acid. In an embodiment, the alkyl ester of the fatty acidis ethyl oleate, isopropyl oleate, ethyl myristate, or isopropylmyristate. In an embodiment, the composition can be in the form of anaqueous, flocculated, injectable suspension. The composition cancomprise additional components, such as a polyoxyethylene derivative ofa sorbitan ester of a carboxylic acid, wherein the carboxylic acidcomprises 8-20 carbon atoms (e.g., polysorbate 20). The pharmaceuticalcomposition can be injectable.

These pharmaceutical compositions can take a variety of forms. Suchforms include, but are not limited to, completely dispersed andflocculated systems.

As described below, the pharmaceutical compositions described hereinhave a number of advantages. For example, the compositions can be easilyresuspended by the user, e.g., through shaking by hand, in a short timeprior to administration. In another example, the pharmaceuticalcompositions, e.g., flocculated systems, can be used to improve thelocal tissue reaction of antipsychotic drugs in extended releaseformulations. By mitigating the adverse results associated with theinjection of these drugs, drug compliance will be greatly improved.

In an aspect, provided herein is a pharmaceutical compositioncomprising:

(a) a water-insoluble antipsychotic agent;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid;

(c) a polyoxyethylene derivative of a sorbitan ester of a carboxylicacid, wherein the carboxylic acid comprises 8-20 carbon atoms; and

(d) an aqueous vehicle;

wherein the composition forms an aqueous, flocculated, injectablesuspension.

In an embodiment, the pharmaceutical composition has a water-insolubleantipsychotic agent that is aripiprazole, a compound of formula I, or acompound of formula II, or pharmaceutically acceptable salts, hydrates,or solvates thereof:

wherein

R^(a) is absent, and R^(b) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂or —C(O)R¹;

or

R^(b) is absent, and R^(a) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂or —C(O)R¹;

R^(c) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂ or —C(O)R¹;

wherein each R¹ is independently selected from the group consisting ofhydrogen, substituted or unsubstituted aliphatic, and substituted orunsubstituted aryl; and

wherein each R² is selected from the group consisting of substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl;

wherein Y^(⊖) is a pharmaceutically acceptable counterion; and

wherein

represents a single or double bond.

In another embodiment, the pharmaceutical composition has awater-insoluble antipsychotic agent that is Compound A-4 or CompoundA-7:

In another embodiment, the pharmaceutical composition has awater-insoluble antipsychotic agent that is olanzapine, a compound offormula III, a compound of formula IV, or a compound of formula V, orpharmaceutically acceptable salts, hydrates, or solvates thereof:

wherein R^(3a), R^(3b), and R^(3c) are independently —CH₂OC(O)R¹,—CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂, —C(O)R¹ or—C(O)OC(R⁴)(R⁵)—OC(O)(G¹²)_(m)R⁶;

wherein R¹ is independently selected from the group consisting ofhydrogen, substituted or unsubstituted aliphatic, and substituted orunsubstituted aryl;

wherein each R⁴ and R⁵ is independently selected from hydrogen, C₁-C₃alkyl, aryl or substituted aryl;

wherein G¹² is selected from NH, CH₂, —S— or —O—;

wherein m is 0 or 1;

wherein R⁶ is selected from C₁₃-C₂₆-alkyl, substituted C₁₃-C₂₆-alkyl,C₁₃-C₂₆-alkenyl, substituted C₁₃-C₂₆-alkenyl, C₁₃-C₂₆-alkynyl,substituted C₁₃-C₂₆-alkynyl, C₁₃-C₂₆-cycloalkyl, and substitutedC₁₃-C₂₆-cycloalkyl, aryl-C₁₃-C₂₆-alkyl, substituted aryl-C₁₃-C₂₆-alkyl,C₁-C₁₀-aryl, substituted C₁-C₁₀-aryl, heteroaryl-C₁₃-C₂₆-alkyl,substituted heteroaryl-C₁₃-C₂₆-alkyl; optionally substitutedC₁₃-C₂₆-alkylaryl, optionally substituted C₁₃-C₂₆-alkenylaryl andoptionally substituted C₁₃-C₂₆-alkynylaryl; and

wherein Y^(⊖) is a pharmaceutically acceptable counterion.

In yet another embodiment, the pharmaceutical composition has awater-insoluble antipsychotic agent that is

In another embodiment, the pharmaceutical composition has awater-insoluble antipsychotic agent that is lurasidone (compound VI) orpharmaceutically acceptable salts, hydrates, or solvates thereof.

In another embodiment, the pharmaceutical composition containscomponents (b) and (c) at a ratio that results in flocs of component (a)wherein the flocs settle to greater than a predetermined sediment bedheight, such that components (a), (b) and (c) can be resuspended forinjection.

In another embodiment, the pharmaceutical composition has a bed heightthat is at least a 20 to 160% increase in sediment height compared to anon-flocculated composition after 24 hours of undisturbed sitting.

In another embodiment, the pharmaceutical composition has a bed heightthat is at least a 20 to 80% increase in sediment height compared to anon-flocculated composition after 24 hours of undisturbed sitting. Inother embodiments, the bed height has at least a 20 to 150, 20 to 140,20 to 130, 20 to 120, 20 to 110, 20 to 100, 20 to 90, 20 to 70, 20 to60, 20 to 50, 20 to 40 or 20 to 30% increase in sediment height comparedto a non-flocculated composition after 24 hours of undisturbed sitting.

In another embodiment of the pharmaceutical composition, components (a),(b) and (c) that can be resuspended for injection within 1-60 seconds ofhandshaking.

In an embodiment, the pharmaceutical composition contains the ratio ofcomponents (b) to (c) such that the composition can be injected using a20 or greater gauge needle.

In an embodiment, the pharmaceutical composition contains the ratio ofcomponents (b) to (c) that is approximately 2.5 to 1, by weight.

In an embodiment, the pharmaceutical composition contains the ratio ofcomponents (b) to (c) that is approximately 1 to 1, by weight.

In other embodiments, the pharmaceutical composition contains the ratioof components (b) to (c) that is approximately 2.4 to 1, 2.3 to 1, 2.2to 1, 2.1 to 1, 2.0 to 1, 1.9 to 1, 1.8 to 1, 1.7 to 1, 1.6 to 1, 1.5 to1, 1.4 to 1, 1.3 to 1, 1.2 to 1 or 1.1 to 1 by weight.

In another embodiment of the pharmaceutical composition, thepolyoxyethylene derivative of a sorbitan ester (c) is polysorbate 20.

In another embodiment, the pharmaceutical composition comprises about0.2-1 weight percent C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid. In anembodiment, the alkyl ester of the fatty acid is ethyl oleate, isopropyloleate, ethyl myristate, or isopropyl myristate. In other embodiments,the pharmaceutical composition comprises about 0.3-1, 0.4-1, 0.5-1,0.6-1, 0.7-1, 0.8-1, 0.9-1, 0.3-0.9, 0.3-0.7, 0.3-0.6, 0.3-0.5 or0.3-0.4 weight percent C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid. In anembodiment, the alkyl ester of the fatty acid is ethyl oleate, isopropyloleate, ethyl myristate, or isopropyl myristate.

In another embodiment, the pharmaceutical composition comprises about0.05-0.8 weight percent polysorbate 20, about 0.1-0.3 weight percentpolysorbate 20, or comprises about 0.2 weight percent polysorbate 20.

In another embodiment, the pharmaceutical composition comprisesapproximately 15-35, or approximately 20-30 weight percent aripiprazole,or olanzapine, or a compound of formula I, II, III, IV, V, VI, orpharmaceutically acceptable salts, hydrates, or solvates thereof.

In another aspect, provided herein is an injectable pharmaceuticalcomposition comprising:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof, wherein component (a) is in a weight ratio of approximately15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In another aspect, provided herein is an injectable pharmaceuticalcomposition comprising:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof, wherein component (a) is in a weight ratio of approximately20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In an aspect, provided herein is an injectable composition comprising awater-insoluble antipsychotic agent and a C₁₋₆alkyl ester of a C₁₀₋₂₀fatty acid. In an embodiment, the fatty acid is ethyl oleate, isopropyloleate, ethyl myristate, or isopropyl myristate. In an embodiment, theinjectable composition is formulated for modulating tissue reactionassociated with the delivery of a water-insoluble antipsychotic agent isaripiprazole, or olanzapine, or a compound of formula I, II, III, IV, Vor VI, compounds A-4 or A-7, O-56, O-111, O-112, O-7, O-8 and O-9.

In an embodiment, the injectable composition is formulated formodulating tissue reaction through a reduction in the irritation at thesite of injection. In another embodiment, the injectable compositionfurther comprises a surfactant, wherein the surfactant is polysorbate 20and also comprises a buffer wherein the buffer is a phosphate, citrate,tartrate or acetate buffer.

In another embodiment, the pharmaceutical composition comprises awater-insoluble antipsychotic agent, about 0.2-1% percent of a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate, isopropyloleate, ethyl myristate, or isopropyl myristate, and about 0.05-0.8%percent of polysorbate 20 and phosphate buffer.

In another embodiment, a method for treating disorders of the centralnervous system is provided by administering an effective amount of thepharmaceutical composition to an individual in need of such treatment.In another embodiment the disorder is anxiety or depression, bipolardisorder, autism-related irritability, a psychotic condition,schizophrenia or schizophreniform diseases, or acute mania.

DETAILED DESCRIPTION OF INVENTION

Pharmaceutical Compositions

Provided herein is an injectable pharmaceutical composition comprisingan antipsychotic agent, a C₁₋₆ alkyl ester of a C₁₀₋₂₀ fatty acid, e.g.,ethyl oleate, isopropyl oleate, ethyl myristate, or isopropyl myristate,and a polyoxyethylene derivative of a sorbitan ester of a carboxylicacid, wherein the carboxylic acid comprises 8-20 (e.g., 11-13) carbonatoms. This composition is particularly useful for the formulation of awater-insoluble antipsychotic agent into an injectable pharmaceuticalcomposition. In an embodiment, the polyoxyethylene derivative ispolysorbate 20. The pharmaceutical composition can further comprise andaqueous vehicle, such as phosphate buffered saline, as well as any ofthe pharmaceutical components described herein.

The compositions described herein possess a number of advantages. Forexample, the compositions offer minimized excipient levels whileco-optimizing both resuspendability and acceptable injectability, andmaintain good physiochemical attributes of the antipsychotic agent. Asdescribed in the experimental section, these properties can bedetermined based on comparisons of vehicle performance based on settledbed height and qualitative ease of resuspension. Briefly, theredispersibility of a pharmaceutical composition can be assessed bypreparing a number of different formulations (antipsychotic agent with avariety of excipients), and comparing the relative height of the settledbeds. In general, higher settled bed heights are indicative offlocculated, or loosely aggregated, particles. These suspensions settlefaster initially, but their loosely aggregated state allows for easierredispersion and better physical stability as the particles cannot packas tightly as fully dispersed suspensions, thereby leading to reducedresuspension times using, for example, shaking by hand. In oneembodiment, the pharmaceutical compositions, e.g., a pharmaceuticalcomposition of components (a) and (b), or (a), (b) and (c), can beresuspended for injection within 1-60 seconds of shaking by hand.

As used herein, the term “flocculation” refers to the formation of aloose aggregation of discrete particles held together in a network-likestructure by physical adsorption of macromolecules, bridging duringchemical interaction (precipitation), or when the longer range van derWaals forces of attraction exceed the shorter range forces ofattraction. (See Pharmaceutical dosage forms: Disperse systems Volume 2.Edited by Herbert A. Lieberman, Martin M. Rieger, and Gilbert S. Banker.(1996) Pg. 18). The “loose aggregation of discrete particles” can bereferred to herein as “flocs.”

Pharmaceutical compositions containing component (b) (a C₁₋₆alkyl esterof a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate, isopropyl oleate, ethylmyristate, or isopropyl myristate) and component (c) (e.g., polysorbate20) have significantly high settled bed height, which, as describedabove, result in improved re-suspendability, and therefore ease of use.As shown in Table 1, this bed height increases as the amount ofC₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid increases. As the bed heightincreases, the time needed for re-suspension decreases. As describedbelow, the flocculation phenomenon is uniquely attributed to theadditional influence of component (b).

Accordingly, in one embodiment, provided herein is a compositioncomprising components (a), (b) and (c) at a ratio that results in flocs,wherein the flocs settle to greater than a predetermined sediment bedheight, such that components (a), (b) and (c) can be resuspended forinjection. The flocs can be comprised of component (a), components (a)and (b), or components (a), (b) and (c). A predetermined sediment bedheight refers to a bed height that is higher than the bed height of acomparative pharmaceutical composition that has none of component (b),or none of components (b) or (c). In one embodiment, the bed height iscomprised of at least a 10, 20, 30, 40, 50, 60, 70, 80, 100% or greaterthan 100% (e.g., about 160%) increase in sediment height compared to anon-flocculated pharmaceutical composition after 24 hours of undisturbedsitting. In another embodiment, the bed height is comprised of at leasta 20 to 160% increase in sediment height compared to a non flocculatedpharmaceutical composition after 24 hours of undisturbed sitting.

In addition to the resuspendability and injectability advantagesdescribed above, the pharmaceutical compositions provided herein canresult in reduced tissue reactions.

Specifically, the composition provided herein results in a decreasedtissue reaction normally associated with antipsychotic agents, such asaripiprazole, olanzapine, derivatives thereof, prodrugs thereof, andsalts thereof.

As used herein, the term “tissue reaction” (TR) refers to foreign bodyresponses to a drug product (active agent and/or vehicle used foradministration). For example, local tissue reaction to drug productresults in the influx of immune cells, the subsequent encapsulation ofthe drug product and usually the development of a fluid filled centralcavity. The presence of fibroblasts, neutrophils, macrophages and giantcells are often observed via histological examination. The term “undueTR” or “unacceptable TR” refers to moderate to severe TR which isunacceptable to the patient and thereby impacts unfavorably on patientcomfort and compliance. The term “reduced TR” refers to generallyminimal to mild TR, which is acceptable to the patient and thereforedoes not engender an adverse event related nor impact unfavorably onpatient compliance. As such, the injectable composition provided hereinis characterized by a decreased undue TR and a more acceptable TRfollowing injection of drug product. In an embodiment, a “tissuereaction” is a form of “injection site reaction.”

The modulation of tissue response following SC administration isdescribed by the reduction of the injection site weight (comprising thedrug depot and surrounding tissue) which provides a quantitativeassessment of the severity of the response. The modulation of the tissueresponse following IM administration is described by the spreadabilityof the drug and resulting depot morphology; spreading of the drug alongthe fascial planes of muscle is desirable rather than the formation of aconcentrated mass of drug in a small area.

Depot morphology resulting from IM injection of aripiprazole andaripiprazole prodrugs has been described. Injections of slow-releasingformulations of drugs, including aripiprazole commonly result in theformation of “cyst-like structures”, characterized by a vascularizedcapsule of roughly spherical shape and comprising various cell types,with or without and a central serous fluid compartment. Tissue responsesto slow-releasing formulations occur as the body mounts an immuneresponse to clear the material from the injection site; this reaction iscommonly referred to as a foreign body response. The spherical nature ofthese reactions can result in localized discomfort and pain, as the FBRincreases in size compressing on nerve fibers innervating muscle tissueand with the release of pro-inflammatory cytokines from the site.

In a particular embodiment, the modulation of the tissue reaction is thereduction in tissue reaction at the site of injection. In oneembodiment, the injection site reaction is reduced by a particularamount, e.g., about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%,etc.

When the antipsychotic agent/polyoxyethylene derivative of a sorbitanester/C₁₋₆ alkyl ester of a C₁₀₋₂₀ fatty acid, composition is to be usedas an injectable composition, including but not limited to injectionthrough a needle or needle-less injection, it can be formulated into aconventional injectable carrier. Suitable carriers include biocompatibleand pharmaceutically acceptable solutions.

As described above, the pharmaceutical composition comprising components(a) and (b) can comprises component (c): a polyoxyethylene derivative ofa sorbitan ester of a carboxylic acid, wherein the carboxylic acidcomprises 8-20 carbon atoms. In a particular embodiment, component (c)is polysorbate 20, sold under the trademark TWEEN®. The polysorbate canbe added in an amount that reduces surface tension of a drug product oraids in suspension stability of the drug product.

Provided below are representative drawings of the polyoxyethylenederivative of a sorbitan ester of a carboxylic acid used in thepharmaceutical compositions:

For compositions comprising components (a), (b), and (c), or (a), (b),(c) and (d), the ratios of (b) and (c) can vary. In one embodiment, theratio of components (b) to (c) is approximately 10 to 0.5, e.g., 10 to1, e.g., 8 to 1, e.g., 0.5 to 1, by weight. In another embodiment, theratio of components (b) to (c) is approximately 2.5 to 1, by weight. Inanother embodiment, the ratio of components (b) to (c) is approximately1 to 1, by weight. In still another embodiment, the compositioncomprises component (a), a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, andpolysorbate 20, wherein the ratio of C₁₋₆alkyl ester of a C₁₀₋₂₀ fattyacid, and polysorbate 20 is approximately 4.5 to 1, by weight. In stillanother embodiment, the composition comprises component (a), C₁₋₆alkylester of a C₁₀₋₂₀ fatty acid, and polysorbate 20, wherein the ratio ofC₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid and polysorbate 20 isapproximately 2.5 to 1, by weight. In another embodiment, thecomposition comprises component (a), C₁₋₆alkyl ester of a C₁₀₋₂₀ fattyacid and polysorbate 20, wherein the ratio of C₁₋₆alkyl ester of aC₁₀₋₂₀ fatty acid and polysorbate 20 is approximately 1 to 1, by weight.In yet another embodiment, the composition comprises component (a),C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid and polysorbate 20, wherein theratio of C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid and polysorbate 20 iswithin the range of approximately 3 to 2-1 to 1, by weight.

For compositions comprising components (a) and (b), (a), (b), and (c),or (a), (b), (c) and (d), the weight percent of (b) and (c) can vary. Inone embodiment, the composition comprises about 0.2-1 weight percentcomponent (b) (a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyloleate, isopropyl oleate, ethyl myristate, or isopropyl myristate).

In another embodiment, the composition comprises about 0.05-0.8 weightpercent component (c), e.g., polysorbate 20. In yet another embodiment,the composition comprises about 0.1-0.3 weight percent component (c),e.g., polysorbate 20. In still another embodiment, the compositioncomprises about 0.2 weight percent polysorbate 20.

In an embodiment, the ratio of components (b) to (c) is such that thecomposition can be injected using a 20-25 gauge needle. For example, theneedle can be a 20, 21, 23 or 23.5 gage needle. In one embodiment, theratio of components (b) to (c) is such that the composition can beinjected through a sieve screen of 150-350 m using a 20-25 gauge needle.In one embodiment, the ratio of components (b) to (c) is such that thecomposition can be injected using a 20 or greater gauge needle.

The compositions provided herein can also have varying amounts ofantipsychosis agent. The antipsychosis agent can be aripiprazole, orolanzapine, salts of these compounds, hydrates of these compounds,and/or prodrugs of these compounds. In one embodiment, the compositioncomprises approximately 15-35 weight percent aripiprazole, orolanzapine, or a compound of formula I, II, III, IV, V or VI(lurasidone), or pharmaceutically acceptable salts, hydrates, orsolvates thereof. In another embodiment, the composition comprisesapproximately 20-30 weight percent aripiprazole, or olanzapine, or acompound of formula I, II, III, IV, V or VI, or pharmaceuticallyacceptable salts, hydrates, or solvates thereof.

The aqueous vehicle of the pharmaceutical compositions provided hereincan be a buffer. The buffer may be selected from a phosphate, citrate,tartrate or acetate buffer. In a particular embodiment, the buffer is aphosphate buffer.

The pharmaceutical compositions provided herein can further compriseadditional components. For example, the use of additional wetting agentsor surfactants in a pharmaceutical composition may promote one or moreof the following:

(1) Surface tension reduction, which may aid in wetting, since a ‘lowersurface tension’ liquid will wet surfaces or particles more readily thana ‘high surface tension’ liquid. Lowering the surface tension of aliquid may also decrease the incidence of foaming. The surface tensionof a liquid will be lower as more surfactant is added;

(2) Formation of micelles (i.e., spherical or non-spherical surfactantstructures in solution that have the capability to dissolve non-solublecomponents); and/or

(3) Increase of suspension physical stability.

The pharmaceutical compositions can also contain an aqueous vehicle,which is a vehicle that dilutes and suspends the drug. The diluent ofinterest herein is one which is pharmaceutically acceptable (safe andnon-toxic for administration to a human) and is useful for thepreparation of a reconstituted formulation. Exemplary diluents includesterile water, sterile water for injection (WFI), bacteriostatic waterfor injection (BWFI), a pH buffered solution (e.g., phosphate-bufferedsaline), sterile saline solution, Ringer's solution or dextrosesolution. The buffer can be phosphate, citrate, tartrate or acetate. Ina particular embodiment, the diluent is phosphate-buffered saline, whichis a water-based salt solution containing either sodium chloride orpotassium chloride, and sodium phosphate or potassium phosphate. In oneembodiment, the phosphate buffer comprises isotonic saline with 5-50 mMphosphate buffer at pH 4.0-9.0, e.g., 5.0-8.0, e.g., 5.0-7.5.

The pharmaceutical compositions can further contain an additionalsurfactant that preferentially adsorbs to an interface between twoimmiscible phases, such as the interface between water and an organicpolymer solution, a water/air interface or organic solvent/airinterface. Suitable surfactants include but are not limited to fattyalcohols such as polyethylene glycols (PEGs) and cetyl alcohol.

Optionally, the pharmaceutical compositions can further comprise adispersant, such as, for example, carboxymethyl cellulose (CMC),carboxymethyl cellulose sodium, cross-linked sodium carboxymethylcellulose, calcium carboxymethyl cellulose, and low substitutedhydroxypropyl cellulose magnesium aluminum silicate, or a mixturethereof. In a particular embodiment, the pharmaceutical compositioncomprises carboxymethyl cellulose.

Further, mono- and diglycerides can be used as excipients for thepharmaceutical compositions provided herein. Examples of commerciallyavailable mono- and diglycerides include: monopalmitolein (C16:1)(Larodan), monoelaidin (trans C18:1) (Larodan), monocaproin (C6)(Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin(Larodan), glyceryl monomyristate (C14) (Nilol MGM, Nikko), glycerylmonooleate (cis C18:1) (PECEOL, Gattefosse), glyceryl monooleate(Myverol, Eastman), glycerol monooleate/linoleate (OLICINE, Gattefosse),glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate(Softigen 701, Huls), glyceryl monolaurate (ALDO MLD, Lonza), glycerolmonopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul GMS,ABITEC), glyceryl mono- and dioleate (Capmul GMO-K, ABITEC), glycerylpalmitic/stearic (CUTINA MD-A, ESTAGEL-G18), glyceryl acetate (LameginEE, Grunau GmbH), glyceryl laurate (Imwitor 312, Huls), glycerylcitrate/lactate/oleate/linoleate (Imwitor) 375, Huls), glycerylcaprylate (Imwitor 308, Huls), glyceryl caprylate/caprate (Capmul MCM,ABITEC), caprylic acid mono- and diglycerides (Imwitor 988, Huls),caprylic/capric glycerides (Imwitor 742, Huls), mono- and diacetylatedmonoglycerides (Myvacet 9-45, Eastman), glyceryl monostearate (Aldo MS,Arlacel 129, ICI), lactic acid esters of mono and diglycerides (LAMEGINGLP, Henkel), dicaproin (C6) (Larodan), dicaprin (C10) (Larodan),dioctanoin (C8) (Larodan), dimyristin (C14) (Larodan), dipalmitin (C16)(Larodan), distearin (Larodan), glyceryl dilaurate (C12) (Capsule GDL,ABITEC), glyceryl dioleate (Capmul GDO, ABITEC), glycerol esters offatty acids (GELUCIRE 39/01, Gattefosse), dipalmitolein (C16:1)(Larodan), 1,2 and 1,3-diolein (C18:1) (Larodan), dielaidin (C18:1)(Larodan), and dilinolein (C18:2) (Larodan). Certain compositions of theapplication can include one or more of the mono- and diglycerides above.

The pharmaceutical compositions may also optionally comprise anantioxidant to inhibit the oxidation of ingredients. Some examples ofantioxidants include, but are not limited to, ascorbic acid, ascorbylpalmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumiso-ascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha-tocopherol, andpropylgallate.

The pharmaceutical compositions can further include a lipid, e.g., aneutral lipid. Neutral lipids include any lipid that remains neutrallycharged at a pH between about 4 and 9. Neutral lipids include, withoutlimitation, cholesterol, other sterols and derivatives thereof,phospholipids, and combinations thereof and other neutral lipids. Thephospholipids include any one phospholipid or combination ofphospholipids capable of forming liposomes. They includephosphatidylcholines, phosphatidylethanolamines, lecithin and fractionsthereof, phosphatidic acid, phosphatidylglycerols,phosphatidylinositols, phosphatidylserines, plasmalogens andsphingomyelins. The phosphatidylcholines include, without limitation,those obtained from egg, soy beans or other plant sources or those thatare partially or wholly synthetic or of variable lipid chain length andunsaturation, POPC, OPPC, natural or hydrogenated soy bean PC, naturalor hydrogenated egg PC, DMPC, DPPC, DSPC, DOPC and derivatives thereof.In one embodiment, phosphatidylcholines are POPC, non-hydrogenated soybean PC and non-hydrogenated egg PC. Phosphatidylethanolamines include,without limitation, DOPE, DMPE and DPPE and derivatives thereof.Phosphatidylglycerols include, without limitation, DMPG, DLPG, DPPG, andDSPG. Phosphatidic acids include, without limitation, DSPA, DMPA, DLPAand DPPA.

The pharmaceutical compositions can also advantageously employ a densityenhancing agent, such as a sugar, e.g., mannitol, or sorbitol and/or atonicity adjusting agent, such as sodium chloride or glycerol.

Other pharmaceutical carriers that could be used in the pharmaceuticalcompositions provided herein also include water, aqueous methylcellulosesolutions, saline, dextrose solutions, fructose solutions, ethanol, oroils of animal, vegetative, or synthetic origin. The pharmaceuticalcarrier may also contain preservatives, and buffers as are known in theart.

The term “pharmaceutical composition”, “formulation”, “injectablecomposition,” etc. are used synonymously throughout the application.

The pharmaceutical compositions described herein may also be in the formof an emulsion. The term “emulsion” as used in this specificationdenotes a two-phase system in which one phase is finely dispersed in theother phase. An emulsifier can be used in the pharmaceuticalcompositions to form the emulsion. The term emulsifier, as used by thisinvention, denotes an agent that can reduce and/or eliminate the surfaceand the interfacial tension in a two-phase system. Such an agentpossesses both hydrophilic and lipophilic groups in the emulsifieragent.

The pharmaceutical compositions described herein may also be in the formof a dispersion. As used herein, the term “dispersion” is to beunderstood as a mixture in which fine particles of one substance (e.g.,a drug) are scattered throughout another substance (e.g., a liquid).Dispersions include suspensions, and colloids.

The methods of the invention include administering the compositionsdescribed herein, thereby obtaining an extended release or sustainedrelease profile in the patient. “Extended-release” or“sustained-release” includes dosage forms whose drug-releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventional dosageforms such as a solution or an immediate release dosage form. Anextended release profile includes deliveries that achieve atherapeutically effective amount of the antipsychotic agent, e.g.,aripiprazole, or olanzapine, or a compound of formula I, II, III, IV orV, is present in the plasma of the individual for at least about 7 days,preferably at least about 14 days, or more preferably at least about 21days alternatively for at least 2, 3, 4, 6 or 8 weeks or as much asthree months.

In one embodiment, the pharmaceutical compositions can be administeredas a single or sole (undivided) dose. However, the composition is alsouseful for those individuals that require constant or chronic therapy,such as those that receive repeated doses over several hours, days,weeks, months, or more. In such dosing regimens, the method can comprisea first administration of a first extended release composition and asecond administration of a second extended release composition. Thesecond composition can be the same, substantially the same or differentas the first and can include the same active agent or a different activeagent. For example, the second composition can be administered at about7 days, or more, such as at least about 14 days, or at least about 17days, after the first administration, where the first administrationresults in the release of agent for a period of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14 days, or more.

The injectable, pharmaceutical compositions described herein can beinjected into a patient in any number of ways. The term “injectable” asused herein refers to a composition that is suitable to be delivered toan individual in an injection, such as with an injection device,including one that employs a syringe or a cartridge, which may be housedin a manual injection device or an auto-injection device, for example.Specifically, the injectable composition is suitable for parenteraladministration. As used herein, the term “parenteral administration”refers to administration through injection or infusion. Parenteraladministration includes, but is not limited to, intravenousadministration, intradermal administration, subcutaneous administrationor intramuscular administration. The term “intravenous administration”means administration into a vein. “Intradermal administration” isinjection into the upper layer of skin (i.e., the dermis), just beneaththe epidermis. “Subcutaneous administration” refers to administrationjust below the skin. “Intramuscular administration” is the injectiondirectly into a muscle.

In another aspect, provided herein is an injectable pharmaceuticalcomposition comprising:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof, wherein component (a) is in a weight ratio of approximately15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In another aspect, provided herein is an injectable pharmaceuticalcomposition comprising:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof, wherein component (a) is in a weight ratio of approximately20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III,IV, V, VI, or pharmaceutically acceptable salts, hydrates, or solvatesthereof in a weight ratio of approximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In addition to the other aspects provided above, also provided herein,also provided herein is an injectable pharmaceutical compositioncomprising:

(a) aripiprazole, compound A-4, or compound A-7, wherein component (a)is in a weight ratio of approximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 15-35%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In another aspect, provided herein is an injectable pharmaceuticalcomposition comprising:

(a) aripiprazole, compound A-4, or compound A-7, wherein component (a)is in a weight ratio of approximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 20-30%;

(b) a C₁₋₆alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyl oleate,isopropyl oleate, ethyl myristate, or isopropyl myristate, in a weightratio of approximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In addition to the other aspects provided above, also provided herein,also provided herein is an injectable pharmaceutical compositioncomprising:

(a) aripiprazole, compound A-4, or compound A-7, wherein component (a)is in a weight ratio of approximately 15-35%;

(b) ethyl oleate or isopropyl myristate, in a weight ratio ofapproximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 15-35%;

(b) ethyl oleate or isopropyl myristate, in a weight ratio ofapproximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 15-35%;

(b) ethyl oleate or isopropyl myristate, in a weight ratio ofapproximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

In another aspect, provided herein is an injectable pharmaceuticalcomposition comprising:

(a) aripiprazole, compound A-4, or compound A-7, wherein component (a)is in a weight ratio of approximately 20-30%;

(b) ethyl oleate or isopropyl myristate, in a weight ratio ofapproximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 20-30%;

(b) ethyl oleate or isopropyl myristate, in a weight ratio ofapproximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.1-0.3%; and

(d) an aqueous carrier.

In an embodiment, the injectable pharmaceutical composition comprises:

(a) aripiprazole, compound A-4, or compound A-7, in a weight ratio ofapproximately 20-30%;

(b) ethyl oleate or isopropyl myristate, in a weight ratio ofapproximately 0.2-1%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

Antipsychotic Agents

As discussed above, the pharmaceutical compositions provided herein areuseful for the administration of antipsychotic drugs to a subject. Asused herein the term “antipsychotic” refers all drugs used to treatpsychosis. Common conditions for which antipsychotics are prescribedinclude schizophrenia, mania and delusional disorder, althoughantipsychotics are also used to counter psychosis associated with a widerange of other diagnoses. Antipsychotics also act as mood stabilizersmaking them suitable for the treatment of bipolar disorder (even when nosymptoms of psychosis are present). The pharmaceutical compositionsprovided herein are particularly useful for formulating awater-insoluble antipsychotic into an injectable composition.

The pharmaceutical compositions described herein are useful foradministration of water-insoluble antipsychotic agents. As used herein,a water-insoluble antipsychotic agent is one that dissolves in aquantity of water to an extent of less than 100%. The term“water-insoluble” does not necessarily refer to complete or 100%water-insolubility. In certain embodiments, the water-insoluble materialdissolves to an extent of less than 50%. In other embodiments, thewater-insoluble material dissolves to an extent of less than 10%. In aparticular embodiment, the water-insoluble material dissolves to anextent of less than 1%. The term “water-insoluble” can refer tosolubility as prescribed in the United States Pharmacopoeia.

In one embodiment, the antipsychotic drug of the pharmaceuticalcomposition is aripiprazole. The aripiprazole drug substance cancomprise, consist essentially of, or consist of aripiprazole (in acrystalline, non-crystalline or amorphous form), an aripiprazole salt,an aripiprazole solvate (including ethanolates and hydrates), or otheraripiprazole polymorphs. Preferred salts include those salts insolublein an aqueous vehicle. Pharmaceutical salts such as the hydrochlorideand various pharmaceutically acceptable carboxylate salts are suitable.

The aripiprazole drug substance can also include aripiprazole prodrugs.The term “prodrug” is art-recognized and is intended to encompasscompounds which, under physiological conditions, are converted intoactive compounds, e.g., those described herein. A common method formaking a prodrug is to select moieties which are hydrolyzed or otherwisecleaved under physiological conditions to provide the desired compound.In other embodiments, the prodrug is converted by an enzymatic activityof the host animal.

Preferred aripiprazole prodrugs that can be used in the pharmaceuticalcompositions include the prodrugs described in U.S. Publication No.2011/0003828, which is incorporated herein by reference in its entirety.

In a particular embodiment, the aripiprazole prodrug is a compound offormula (I) or formula (II):

wherein

R^(a) is absent, and R^(b) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂or —C(O)R¹;

or

R^(b) is absent, and R^(a) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂or —C(O)R¹;

R^(c) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂ or —C(O)R¹;

wherein each R¹ is independently selected from the group consisting ofhydrogen, substituted or unsubstituted aliphatic, and substituted orunsubstituted aryl; and

wherein each R² is selected from the group consisting of substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl;

wherein Y^(⊖) is a pharmaceutically acceptable counterion; and

wherein

represents a single or double bond.

Suitable counterions include, e.g., chloride, bromide, iodide, sulfate,phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate,lactate, maleate, fumarate, camsylate, glucepate, mesylate, napsylate,pamoate, conjugate bases of organic carboxylic acids, and the like.

In one embodiment of formula (I), the aripiprazole prodrug is a compoundof formula (I′):

wherein R^(a) is CH₂OC(O)R¹ and wherein R¹ is selected from substitutedor unsubstituted aliphatic.

In a particular embodiment of formula (I′), R¹ is —CH₂OC(O)—(CH₂)₄CH₃(Compound A-4). In another particular embodiment of formula (I′), R¹ is—CH₂OC(O)—(CH₂)₁₀CH₃ (Compound A-7). Compounds A-4 and A-7 are depictedbelow:

In another embodiment, the antipsychotic drug of the pharmaceuticalcomposition is olanzapine. The olanzapine drug substance can comprise,consist essentially of, or consist of olanzapine (in a crystalline,non-crystalline or amorphous form), an olanzapine salt, an olanzapinesolvate (including for example ethanolates and hydrates), or otherolanzapine polymorphs. A preferred olanzapine salt is olanzapinepamoate. The antipsychotic drug can also be an olanzapine prodrug.

The olanzapine drug substance can also include olanzapine prodrugs ofFormula (III), (IV) or (V):

wherein R^(3a), R^(3b) and R^(3c) are independently —CH₂OC(O)R¹,—CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂, —C(O)R¹ or—C(O)OC(R⁴)(R⁵)—OC(O)(G¹²)_(m)R⁶;

wherein R¹ is independently selected from the group consisting ofhydrogen, substituted or unsubstituted aliphatic, and substituted orunsubstituted aryl;

wherein each R⁴ and R⁵ is independently selected from hydrogen, C₁-C₃alkyl, aryl or substituted aryl; preferably, hydrogen or methyl;

wherein G₁₂ is selected from NH, CH₂, —S— or —O—;

wherein m is 0 or 1;

wherein R⁶ is selected from C₁₃-C₂₆-alkyl, substituted C₁₃-C₂₆-alkyl,C₁₃-C₂₆-alkenyl, substituted C₁₃-C₂₆-alkenyl, C₁₃-C₂₆-alkynyl,substituted C₁₃-C₂₆-alkynyl, C₁₃-C₂₆-cycloalkyl, and substitutedC₁₃-C₂₆-cycloalkyl, aryl-C₁₃-C₂₆-alkyl, substituted aryl-C₁₃-C₂₆-alkyl,C₁-C₁₀-aryl, substituted C₁-C₁₀-aryl, heteroaryl-C₁₃-C₂₆-alkyl,substituted heteroaryl-C₁₃-C₂₆-alkyl; optionally substitutedC₁₃-C₂₆-alkylaryl, optionally substituted C₁₃-C₂₆-alkenylaryl andoptionally substituted C₁₃-C₂₆-alkynylaryl; and

wherein Y^(⊖) is a pharmaceutically acceptable counterion.

Suitable counterions include, e.g., chloride, bromide, iodide, sulfate,phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate,lactate, maleate, fumarate, camsylate, glucepate, mesylate, napsylate,pamoate, conjugate bases of organic carboxylic acids, and the like.

In one embodiment of formula (III), R^(3a) is —C(O)OCH₂OC(O)R⁶ and R⁶ isselected from C₁₃-C₂₆-alkyl. In a particular embodiment of formula(III), R^(3a) is —C(O)OCH₂OC(O)(CH₂)₁₄CH₃ (Compound O-56). In anotherparticular embodiment of formula (III), R^(3a) is—C(O)OCH₂OC(O)(CH₂)₁₆CH₃ (Compound O-111). In still another particularembodiment of formula (III), R^(3a) is —C(O)OCH₂OC(O)(CH₂)₁₈CH₃(Compound O-112). Compounds O-56, O-111 and O-112 are depicted below:

In one embodiment of formula (IV), R^(3b) is —C(O)OCH₂OC(O)R⁶ and R⁶ isselected from C₁₃-C₂₆-alkyl. In a particular embodiment of formula (IV),R^(3b) is —C(O)OCH₂OC(O)(CH₂)₁₄CH₃ (Compound O-7). In another particularembodiment of formula (IV), R^(3b) is —C(O)OCH₂OC(O)(CH₂)₁₆CH₃ (CompoundO-8). In still another particular embodiment of formula (IV), R^(3b) is—C(O)OCH₂OC(O)(CH₂)₁₈CH₃ (Compound O-9). Compounds O-7, O-8 and O-9 aredepicted below:

In another embodiment, the antipsychotic drug of the pharmaceuticalcompositions is lurasidone. Lurasidone is an atypical antipsychotic thatis useful for the treatment of a variety of psychiatric disorders,including schizophrenia and bipolar disorder. This compound is describedin, e.g., U.S. Pat. No. 5,532,372, which is incorporated herein byreference. Lurasidone is the generic name of the compound(3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl]methyl}cyclohexyl)methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione:

The lurasidone drug substance can comprise, consist essentially of, orconsist of lurasidone free base (in a crystalline, non-crystalline oramorphous form), a lurasidone salt, a lurasidone solvate (including forexample ethanolates and hydrates), or other lurasidone polymorphs. Thelurasidone drug substance can also include lurasidone prodrugs.

Accordingly, aripiprazole, or olanzapine, or a compound of formula I,II, III, IV, V or VI can be referred to as an “antipsychotic agent.”

An “aliphatic group” or “aliphatic” is non-aromatic moiety that may besaturated (e.g. single bond) or contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic, contain carbon, hydrogen or,optionally, one or more heteroatoms and may be substituted orunsubstituted.

An aliphatic group, when used as a linker, preferably contains betweenabout 1 and about 24 atoms, more preferably between about 4 to about 24atoms, more preferably between about 4 to about 12 atoms, more typicallybetween about 4 and about 8 atoms. An aliphatic group, when used as asubstituent, preferably contains between about 1 and about 30 atoms,more preferably between about 4 to about 19 atoms. In addition toaliphatic hydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may include alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl groups described herein.

In certain embodiments, the aliphatic groups of the present inventionare alkyl chains containing from 5 to 11 carbon atoms. In otherembodiments, the aliphatic groups are alkyl chains containing from 15 to19 carbon atoms.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl. In an embodiment, aryl is unsubstituted orindependently substituted one or more times with halogen, C₁₋₆alkyl, orO—C₁₋₆alkyl.

The term “heteroaryl” embraces unsaturated heterocyclyl radicals.Examples of heteroaryl radicals include unsaturated 3 to 6 memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The term “compound” is defined herein to include pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, enantiomers,diastereoisomers, racemates and the like of the compounds having aformula as set forth herein.

Methods of Treatment

The pharmaceutical compositions provided herein can be used fortreatment of a variety of disorders in a subject in need thereof. Forexample, the disclosed compositions may be used to treat conditionsselected from: disorders such as cerebral deficit subsequent to cardiacbypass surgery and grafting, stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemicneuronal damage, dementia (including AIDS-induced dementia), Alzheimer'sdisease, Huntington's Chorea, amyotrophic lateral sclerosis, oculardamage, retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, cerebraldeficits secondary to prolonged status epilepticus, migraine (includingmigraine headache), urinary incontinence, substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.), psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, social phobia, obsessive compulsive disorder,and post-traumatic stress disorder (PTSD)), attention deficit disorder(ADD), attention deficit hyperactivity disorder (ADHD), mood disorders(including depression, mania, bipolar disorders), circadian rhythmdisorders (including jet lag and shift work), trigeminal neuralgia,hearing loss, tinnitus, macular degeneration of the eye, emesis, brainedema, pain (including acute and chronic pain states, severe pain,intractable pain, neuropathic pain, inflammatory pain, andpost-traumatic pain), tardive dyskinesia, sleep disorders (includingnarcolepsy), attention deficit/hyperactivity disorder, and conductdisorder.

In another embodiment, the present invention provides a method oftreating cardiac and cardiovascular disorders such as angina,arrhythmia, and hypertension, in a patient in need thereof. The methodcomprises administering to the subject a therapeutically effectiveamount of a composition of the invention or a pharmaceuticallyacceptable salt thereof.

The invention further relates to the treatment of fever, diabetes,allergy, asthma, infection, inflammation, and ulcers in a patient inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a composition of the invention or a pharmaceuticallyacceptable salt thereof.

The invention further relates to the treatment of sleep modulationcomprising administration of a composition of the invention. Sleepmodulation includes decreasing the time to sleep onset, increasing theaverage sleep bout length, and increasing the maximum sleep bout length.

In a particular embodiment, the pharmaceutical compositions describedherein can be used to treat anxiety, depression, bipolar disorder,autism-related irritability, and psychotic conditions including acutemania, schizophrenia and schizophreniform diseases in a subject.

The term “treated,” “treating” or “treatment” includes the diminishmentor alleviation of at least one symptom associated with psychosis or arelated CNS disorder. The term “treated,” “treating” or “treatment” asused in reference to a disease or condition shall mean to intervene insuch disease or condition so as to prevent or slow the development of,prevent or slow the progression of, halt the progression of, oreliminate the disease or condition.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with an injection site reaction.

The term “subject” is intended to include animals, which are capable ofsuffering from or afflicted with dementia associated with psychosis or arelated CNS disorder, including, without limitation, psychoticconditions including acute mania, schizophrenia and schizophreniformdisorders, bipolar disorder, anxiety and depression. Examples ofsubjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep,goats, cats, mice, rabbits, rats, and transgenic non-human animals. Incertain embodiments, the subject is a human, e.g., a human sufferingfrom, at risk of suffering from, or potentially capable of sufferingfrom any of the diseases described herein.

The term “about” or “approximately” usually means within 20%, morepreferably within 10%, and most preferably still within 5% of a givenvalue or range. Alternatively, especially in biological systems, theterm “about” means within about a log (i.e., an order of magnitude),preferably within a factor of two of a given value.

In one embodiment, a therapeutically effective amount of the agent isgiven to a subject using the pharmaceutical compositions providedherein. The term “therapeutically effective amount” is further meant todefine an amount resulting in the improvement of any parameters orclinical symptoms. The actual dose may vary with each patient and doesnot necessarily indicate a total elimination of all disease symptoms. Inthe case of antipsychotics, the management of exacerbations andmaintenance of remission of psychiatric symptoms are main goals oftherapy, and selection of the appropriate drug and dosage in aparticular disease balances these goals with the minimization of adverseevents attributable to the drug.

A therapeutically effective amount of the compound used in the treatmentdescribed herein can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective dose, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

Preferred suitable dosages for the compounds used in the treatmentdescribed herein are on the order of about 1 mg to about 600 mg,preferably about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 90, 95, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280,300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560,580 to about 600 mgs total of active. Dosing schedules may be adjustedto provide the optimal therapeutic response. For example, administrationcan be one to three times daily for a time course of one day to severaldays, weeks, months, and even years, and may even be for the life of thepatient. Practically speaking, a unit dose of any given composition usedin the treatment described herein can be administered in a variety ofdosing schedules, depending on the judgment of the clinician, needs ofthe patient, and so forth. The specific dosing schedule will be known bythose of ordinary skill in the art or can be determined experimentallyusing routine methods. Exemplary dosing schedules include, withoutlimitation, administration five times a day, four times a day, threetimes a day, twice daily, once daily, every other day, three timesweekly, twice weekly, once weekly, twice monthly, once monthly, and soforth. Unit dose preparations provided herein can contain aripiprazole,a compound of Formula I or a compound of Formula II in the range ofabout 60 to about 800 mgs (aripiprazole base equivalents). Unit dosepreparations provided herein can contain olanzapine, a compound ofFormula III, a compound of Formula IV or a compound of Formula V in therange of 40 to about 500 mgs (olanzapine base equivalents). Unit dosepreparations provided herein can contain a compound of Formula VI in therange of 160 to about 1000 mgs (lurasidone base equivalents).

Preferred amounts according to the selected mode of administration areable to be determined by one skilled in the art. Pharmaceuticalcompositions can be manufactured utilizing techniques known in the art.Typically the therapeutically effective amount of the compound will beadmixed with a pharmaceutically acceptable carrier.

EXEMPLIFICATION OF THE INVENTION

The invention is further illustrated by the following examples andprophetic examples. These examples and prophetic examples should not beconstrued as further limiting.

Example I—Formulation Optimization of Antipsychotic Drug Product

The addition of a C₁₋₆ alkyl ester of a C₁₀₋₂₀ fatty acid, e.g., ethyloleate, isopropyl oleate, ethyl myristate, or isopropyl myristate,(0.2-0.5%) and polysorbate 20 (0.2%) affects bed height, as shown inTable 1 (fixed drug load=21.9 wt % (180 mg/mL aripiprazole)).

TABLE 1 % change in height bed/total bed height vs height after sample 5with Experiment 24 hours only PS20 1  6.0 mg Et-oleate 0.2% PS20/0.2%Et- 0.796 +153% oleate 2 15.1 mg Et- 0.2% PS20/0.5% Et- 0.779 +147%oleate oleate 3  6.2 mg i-PrO- 0.2% PS20/0.2% i- 0.755 +140% myristatePrO-myristate 4 15.0 mg i-PrO- 0.2% PS20/0.5% i- 0.846 +169% myristatePrO-myristate 5 (Control) no oily vehicle 0.2% PS20 0.315 — added

Example II—Prodrug Synthesis Procedures

Synthesis of Aripiprazole Prodrugs

Compound A-1: Preparation of7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one

A mixture of Aripiprazole (20 g, 45 mmol), triethylamine (1 mL, 7.1mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide(200 mL) was heated to 80° C. for 20 h. The reaction mixture was cooled,diluted with ethyl acetate (400 mL) and washed with water/brine (1:1,3×500 mL). The organic phase was dried over MgSO₄, filtered andevaporated to dryness under vacuum to give hemi-aminal A-1 as a whitesolid (18.6 g, containing 25% Aripiprazole, 65% yield based on A-1).

Compound 1:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylacetate

A solution of Compound A-1 (50.63 g, 0.105 mol) in anhydroustetrahydrofuran (THF, 80 mL) was treated with acetic anhydride (15.3 mL,0.16 mol) and heated for 2.0 hours at 60° C. (oil-bath). To the abovesolution, triethylamine (2.0 mL, 0.014 mol) was added and stirred for 16hours at 60° C. The solvent was removed using a rotator evaporator. Tothe resulting crude mixture, ethyl acetate (150 mL) and heptane (50 mL)was added. The solution was washed with NaHCO₃ (5% aqueous solution, 250mL). After separation of the two layers, pH of the aqueous layer wasadjusted to above 7. The aqueous layer was further extracted using theorganic mixture. The organic layer was separated and washed with 5%NaHCO₃ solution, followed by deionized water, and brine. The solutionwas dried using anhydrous MgSO₄, filtered and evaporated under vacuum.The resulting product was purified using silica gel columnchromatography using ethanol: ethyl acetate (5:95) as the eluent.Fractions containing the desired product were combined and d-tartaricacid (12.5 g dissolved in 60:5 ethanol:water) was added, resulting inthe precipitation of the desired product (48.78 g, 89% yield). ¹H NMR(CDCl₃, 300 MHz) δ 1.73 (m, 2H), 1.84 (m, 2H), 2.12 (s, 3H), 2.50 (t,2H), 2.68 (m, 6H), 2.87 (dd, 2H), 3.08 (m, 4H), 3.98 (t, 2H), 5.91 (s,2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.08 (dd, 1H), 7.15 (m, 2H).

Compound A-7:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate

Compound A-7 was prepared in an analogous fashion to Compound 1. Thedesired product was isolated as a crystalline solid (0.3 g, 21% yield).The molecular weight was confirmed by mass spectrometer analysis. ¹H NMR(CDCl₃, 300 MHz) δ 0.87 (t, 3H), 1.24 (m, 16H), 1.62 (m, 2H), 1.83 (m,2H), 1.86 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H), 2.68 (m, 6H), 2.86 (dd,2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6.96 (dd,1H), 7.07 (dd, 1H), 7.14 (m, 2H).

Compound A-28:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbenzylcarbamate

To a solution of hemi-aminal A1 (4 g, 8.4 mmol), 4-dimethylaminopyridine(0.15 g, 1.3 mmol) and triethylamine (1.1 mL, 7.5 mmol) indichloromethane (30 mL) was added benzylisocyanate (1.03 mL, 8.3 mmol)and the reaction mixture stirred for 24 hours. The reaction mixture wasthen heated at 35° C. for 20 hours, cooled and washed with water/brine(1:1, 50 mL). The organic phase was dried over MgSO₄, filtered andevaporated under vacuum. The residue was further purified bychromatography on silica eluting with ethylacetate/dichloromethane/methanol (1:1:0.1) to give the desired productas an off white foam (530 mg, 14% yield). ¹H NMR (CDCl₃, 300 MHz) δ1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H),300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H),6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16(m, 1H), 7.23-7.35 (m, 6H); m/z (M⁺H) 611.12 and 613.10.

Compound A-4:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexanoate

Compound A-4 was prepared in an analogous fashion to Compound A-28. Thedesired product was isolated as a yellow solid (3.69 g, 87% yield). ¹HNMR (CDCl₃, 300 MHz) δ 0.78 (t, 3H), 1.11-1.28 (m, 4H), 1.40-1.78 (m,6H), 2.20-2.40 (m, 4H), 2.40-2.60 (m, 6H), 2.73-2.81 (m, 2H), 2.85-3.00(m, 4H), 3.88-4.00 (m, 2H), 5.75-5.83 (m, 2H), 6.55-6.62 (m, 2H),7.03-7.12 (m, 2H), 7.20-7.26 (m, 2H). m/z (M⁺H) 576.4 and 578.4.

Olanzapine Prodrugs

Synthesis of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A]

To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and oncea clear solution formed, the reaction was cooled to 5° C. To this wasadded chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes.The reaction was stirred at room temperature for 30 min and allowed towarm to room temperature. After 15 min at room temperature the reactionmixture was diluted with dichloromethane (100 mL), then washed with aqsatd NaHCO₃ (75 mL) and water (350 mL). The organic phase was dried overMgSO₄ and filtered. The organic phase was then concentrated under vacuumat 45° C. to a volume of −150 mL. The mixture was diluted with ethylacetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. Themixture was cooled to room temperature and the resulting solidprecipitate filtered and washed with ethyl acetate. After drying undervacuum at 35° C. for 90 min chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A](17.1 g, 73%) was obtained as a yellow solid. ¹H-NMR (300 MHz, CDCl₃)δ 7.62-7.14 (4H, m), 6.27-6.22 (1H, m), 5.84-5.69 (1H, m), 5.47-5.23(1H, m), 3.89-3.63 (4H, m), 2.66-2.22 (10H, m).

General Procedure for the synthesis of aliphatic carboxylic acidsubstituted compounds derived from [A]:

To a solution of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A] (1 equiv) in dimethylformamide ((13 mL/g of [A])) was added cesiumcarbonate (1 equiv) and the appropriate aliphatic carboxylic acid (2equiv). The reaction mixture was heated at 60° C. for 2-6 h, untilstarting material [A] had been consumed (loss of starting materialdetermined by TLC). The reaction mixture was cooled, diluted withsaturated aqueous NaHCO₃ (50 mL/g of [A]) and diethyl ether (75 mL/g of[A]). After being stirred for 15 min the mixture was filtered throughcelite and the organic phase separated. This was dried over MgSO₄ andevaporated. The residue was purified by column chromatography on silicaeluting with 30% THF in EtOAc and the product containing fractioncombined and evaporated. The residue was co-evaporated from hexanes.

Compound O-56: (palmitoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Using the procedure as described above with the exception of heating at60° C. for 1 day gave (palmitoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.51 g, 75%) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.62-7.55 (1H,m), 7.45-7.21 (2H, m), 7.17-7.08 (1H, m), 6.26-6.20 (1H, m), 5.66-5.35(2H, m), 3.90-3.79 (2H, m), 3.68-3.54 (2H, m), 2.47-2.45 (4H, m),2.33-2.24 (8H, m), 1.61-1.50 (2H, m), 1.35-1.15 (24H, m), 0.92-0.81 (3H,m)

Compound O-111: (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Using the procedure as described above gave (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.51 g, 75%) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H,m), 7.46-7.37 (1H, m), 7.36-7.26 (1H, m), 7.18-7.07 (1H, m), 6.28-6.19(1H, m), 5.67-5.56 (1.5H, m), 5.38-5.34 (1H, m), 3.91-3.78 (2H, m),3.69-3.54 (2H, m), 2.50-2.40 (4H, m), 2.31-2.24 (6H, m), 1.61-1.50 (2H,s), 1.34-1.20 (30H, m), 0.87 (3H, t). [M+H]⁺=653.14.

Compound O-112: (icosanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Using the procedure as described above gave (icosanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.51 g, 75%) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H,m), 7.46-7.37 (1H, m), 7.36-7.26 (1H, m), 7.18-7.07 (1H, m), 6.28-6.19(1H, m), 5.67-5.57 (1.5H, m), 5.37-5.34 (1H, m), 3.90-3.78 (2H, m),3.69-3.53 (2H, m), 2.49-2.40 (4H, m), 2.32-2.24 (6H, m), 1.61-1.50 (2H,s), 1.34-1.20 (34H, m), 0.87 (3H, t). [M+H]⁺=681.19.

General Procedure for the Synthesis of Compounds 7-9 Synthesis ofchloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate[C]

To a solution of olanzapine (5.0 g, 16 mmol) in tetrahydrofuran (50 mL)at −78° C. was added tetramethylethylenediamine (2.4 mL, 16 mmol),followed by 2M n-BuLi in hexanes (8.0 mL, 16 mmol) over 5 min. Thereaction mixture was stirred for 15 min and then chloromethylchloroformate (2.1 mL, 24 mmol) added and the reaction mixture stirred afurther 30 min. The reaction mixture was then warmed to roomtemperature, stirred for 1 h and quenched with water (50 mL). Thismixture was diluted with brine (50 mL) and extracted with ethyl acetate(50 mL). The organic phase was dried over MgSO₄, evaporated and theresidue further purified by column chromatography on silica eluting with0.2:1:1 methanol/dichloromethane/ethyl acetate to give chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate[C](5.6 g, ˜50% pure by ¹H NMR and LCMS). This was used directly in thenext reaction without further purification. ¹H-NMR (300 MHz, CDCl₃) δ7.02-7.30 (4H, m), 6.45 (1H, s), 5.78-5.92 (1.5H, m), 5.52-5.60 (0.5H,m), 3.50-3.70 (4H, m), 2.35-2.55 (7H, m), 2.32 (3H, s). [M+H]⁺=405.0

General Procedure for the Synthesis of Aliphatic Carboxylic AcidSubstituted Compounds Derived from [C]:

To a solution of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-100H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(C:1 equiv) in dimethylformamide (13 mL/g of [C]) was added Cs₂CO₃ (1equiv) and the appropriate aliphatic carboxylic acid (2 equiv). Thereaction mixture was heated at 65° C. for 2-6 h, until starting material[A] had been consumed (loss of starting material determined by TLC). Thereaction mixture was cooled, diluted with saturated aqueous NaHCO₃ (50mL/g of [C]) and ethyl acetate (75 mL/g of [C]). After being stirred for15 min the mixture was filtered through celite and the organic phaseseparated. This was dried over MgSO₄ and evaporated. The residue wasfurther purified by column chromatography on silica eluting with 1:9methanol/ethyl acetate and after evaporation of the product containingfractions, the residue was co-evaporated with hexane (2×10 mL/g [C]).

Compound O-7: (hexadecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate

Using the general procedure described above, employing palmitic acid and1.0 g of the intermediate [C], provided (hexadecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound O-7) (1.60 g, 39% yield) as a pale yellow oil. ¹H-NMR (300MHz, CDCl₃) δ 7.00-7.25 (4H, m), 6.43 (1H, s), 5.62-5.90 (2H, m),3.51-3.66 (4H, m), 2.30-2.56 (10H, m), 1.58-1.68 (2H, m), 1.20-1.34(26H), 0.87 (3H, t). [M+H]⁺=625.07.

Compound O-8: (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate

Using the general procedure described above, employing stearic acid and2.8 g of the intermediate [C], provided (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-100H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound O-8) (1.44 g, 32% yield) as a pale yellow oil. ¹H-NMR (300MHz, CDCl₃) δ 6.99-7.22 (4H, m), 6.43 (1H, s), 5.62-5.88 (2H, m),3.51-3.66 (4H, m), 2.30-2.66 (10H, m), 1.55-1.70 (2H, m), 1.20-1.34(30H), 0.87 (3H, t). [M+H]⁺=653.21.

Compound O-9: (arachidoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate

Compound O-9 can be made using the general procedure described above,and by employing arachidic acid and the intermediate [C], which couldthen provide (arachidoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound O-9).

The invention claimed is:
 1. A pharmaceutical composition consisting of:(a) compound A-7:

(b) an alkyl ester of a fatty acid, wherein the alkyl ester of a fattyacid is isopropyl myristate; (c) polysorbate 20; and (d) an aqueousvehicle selected from the group consisting of sterile water,bacteriostatic water for injection, sterile saline solution, Ringer'ssolution, dextrose solution, phosphate buffer, citrate buffer, tartratebuffer, and acetate buffer; wherein the composition forms an aqueous,flocculated, injectable suspension.
 2. The composition of claim 1,wherein (b) and (c) are present at a ratio that results in flocscomprising component (a) wherein the flocs settle to greater than apredetermined sediment bed height, such that components (a), (b) and (c)can be resuspended for injection.
 3. The composition of claim 2, whereinthe bed height is comprised of at least a 20 to 160% higher sedimentheight compared to a non-flocculated composition after 24 hours ofundisturbed sitting.
 4. The composition of claim 2, wherein the ratio of(b) to (c) is such that the composition can be injected using a 20 orgreater gauge needle.
 5. The composition of claim 2, wherein the ratioof (b) to (c) is approximately 2.5 to 1, by weight.
 6. The compositionof claim 2, wherein the ratio of (b) to (c) is approximately 1 to 1, byweight.
 7. The composition of claim 2, comprising about 0.2-1 weightpercent isopropyl myristate.
 8. The composition of claim 2, comprisingabout 0.05-0.8 weight percent polysorbate
 20. 9. The composition ofclaim 2, wherein the concentration of (a) is approximately 15-35 weightpercent.
 10. An injectable pharmaceutical composition consisting of: (a)compound A-7:

(b) isopropyl myristate; (c) polysorbate 20; and (d) an aqueous carrierselected from the group consisting of sterile water, bacteriostaticwater for injection, sterile saline solution, Ringer's solution,dextrose solution, phosphate buffer, citrate buffer, tartrate buffer,and acetate buffer.
 11. The injectable pharmaceutical composition ofclaim 10 comprising: (a) approximately 15-35 weight percent compoundA-7; (b) approximately 0.2-1 weight percent isopropyl myristate; and (c)approximately 0.05-0.8 weight percent polysorbate
 20. 12. Apharmaceutical composition consisting of: (a) 20-30 weight percentcompound A-7:

(b) 0.2-1 weight percent isopropyl myristate; (c) 0.05-0.8 weightpercent polysorbate 20; and (d) an aqueous carrier selected from thegroup consisting of sterile water, bacteriostatic water for injection,sterile saline solution, Ringer's solution, dextrose solution, phosphatebuffer, citrate buffer, tartrate buffer, and acetate buffer.
 13. Thecomposition of claim 2, comprising about 0.2-0.5 weight percentisopropyl myristate.
 14. The composition of claim 1, wherein the sterilesaline solution is a phosphate-buffered saline.
 15. The composition ofclaim 10, wherein the sterile saline solution is a phosphate-bufferedsaline.
 16. The composition of claim 12, wherein the sterile salinesolution is a phosphate-buffered saline.